Analysis of fungal bloodstream infection in intensive care units in the Meizhou region of China: species distribution and resistance and the risk factors for patient mortality

doi:10.21203/rs.2.12729/v2

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Analysis of fungal bloodstream infection in intensive care units in the Meizhou region of China: species distribution and resistance and the risk factors for patient mortality

https://doi.org/10.21203/rs.2.12729/v2

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published 14 Aug, 2020

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Background : Fungal bloodstream infections (FBI) among intensive care unit (ICU) patients are increasing. Our objective was to characterize the fungal pathogens that cause bloodstream infections and determine the epidemiology and risk factors for patient mortality among ICU patients in Meizhou, China. Methods Eighty-one ICU patients with FBI during their stays were included in the study conducted from January 2008 to December 2017. Blood cultures were performed and the antimicrobial susceptibility profiles of the resulting isolates were determined. Logistic multiple regression and receiver operating characteristics (ROC) curve analysis were used to assess the risk factors for mortality among the cases. Results The prevalence of FBI in ICU patients was 0.38% (81/21,098) with a mortality rate of 35.8% (29/81). Ninety-eight strains of bloodstream-infecting fungi, mainly Candida spp., were identified from these patients. Candida albicans was most common (42.9%). Two strains of C. parapsilosis were no-sensitive to caspofungin, C. glabrata were less than 80% sensitive to azole drugs.. Logistic multiple regression showed that age, serum albumin, Acute Physiology and Chronic Health Evaluation (APACHE) II score, three or more underlying diseases, and length of stay in ICU were independent risk factors for mortality in FBI. ROC curve analysis showed that APACHE II scores > 19 and serum albumin ≤ 25g/L were the best predictors of mortality. Conclusion Candida spp. predominated with high mortality rates among cases of FBI in ICU. Thus, clinical staff should enhance overall patient monitoring and especially monitor fungal susceptibility to reduce mortality rates.

Infectious Diseases

Intensive care unit

ICU

Fungal bloodstream infection

Epidemiology

Mortality risk factors

The incidence of fungal bloodstream infections caused by pathogens such as Candida spp. has increased in recent years, especially in intensive care units (ICUs) [1, 2]. Candida bloodstream infections have been reported to be the fourth highest in-hospital infection [4]. Studies have shown that the incidence of fungal bloodstream infections in ICUs is 0.22–4.1% in developing countries [5–8] and 0.024–0.687% in developed countries [9–11]. These rates appear to coincide with more widespread use of broad-spectrum antibacterial drugs, glucocorticoids, and immunosuppressive agents, as well as the low immunity of ICU patients and use of central venous catheter technology and other invasive procedures; however, early symptoms of fungal bloodstream infection lack specificity, and low culture-positive rates can lead to a misdiagnosis[3].Thus, hospitalization and timely, effective treatment might be delayed, increasing costs and mortality risks.

Understanding species distribution, resistance, and mortality risk factors associated with pathogenic fungi and ICU fungal bloodstream infections is essential for improving our chances of an early diagnosis, early treatment, and a more positive prognosis. The aim of this study was to analyze the distribution, drug sensitivity, and mortality risk factors of ICU fungal bloodstream infections at three tertiary general hospitals in Meizhou, Guangdong Province, China, to provide baseline reference data for diagnosis and treatment of these infections.

Patient selection

Patients with new infections based on a primary disease who were admitted to ICU of three tertiary hospitals in the Meizhou area were included in the study conducted from January 2008 to December 2017. The criteria for diagnosis and treatment of bloodstream infections were referred to "Guidelines for the diagnosis and treatment of invasive fungal infections in critically ill patients (2007)" by the Chinese Medical Association Intensive Care Medicine Association, the patients had failed to respond to antibiotic treatment and tested positive by blood culture for yeast, yeast-like bacteria, and/or mold. We collected basic information on cases, including demographic data (sex, age, etc.), disease factors (diabetes, tumors, cardiovascular disease, COPD, digestive tract diseases, urinary system diseases, hypertension, and three or more combined underlying diseases), physiological indicators (serum albumin, serum urea nitrogen, γ--glutamyl peptidase, and APACHE II scores), invasive operational factors (e.g., tracheal intubation, multilumen catheter, central venous catheter, and catheter indwelling time), and treatment factors (e.g., length of ICU stay, gastrointestinal nutrition, emergency catheterization, blood transfusion, central venous catheter, patients in shock receiving cathecholamines etc, and the combined use of antibiotics).

Culture and laboratory methods

Blood samples that were taken and were cultured using the BACTEC FX400 Automated Blood Culture System (Becton Dickinson, Franklin Lakes, NJ, USA) and the BACTEC Plus/F resin aerobic culture bottle and fungal culture bottle (Becton Dickinson). The VITEK 2-Compact microbial identification and analysis system and yeast biochemical card and analytical profile system systems (bioMérieux, Marcy-l’Étoile, France) were used to identify fungal organisms, using C. albicans ATCC 90028 and C. parapsilosis ATCC22019 as quality control strains.

ATB FUNGUS 3 fungal susceptibility reagent strips (bioMérieux) were used to determine antimicrobial susceptibilities to caspofungin, amphotericin B, fluconazole, voriconazole, and itraconazole on CHROMagar medium (Zhengzhou Biocell, Henan Province, China).

Statistical analyses

Data were analyzed using SPSS 21.0 (IBM Corp., Waltham, NY, USA). Variables that displayed a normal distribution were expressed as the mean ± standard deviation (SD) using one-way analysis of variance. Counts were expressed as the number of cases and their percentage rate and significance was measured using the chi-squared test.

Variables that were significant risk factors or close to statistical significance (P < 0.1) using univariate analysis were included in a two-class logistic multiple regression model for multivariate survival analysis. The best predictive values of independent risk factors for mortality according to related physiological indicators were analyzed using the ROC, where P < 0.05 was considered statistically significant.

Total number of blood culture inspections and fungal isolation rates in ICU from 2008 to 2017

The overall prevalence of ICU bloodstream infections was 6.54% (1,380/21,098 blood cultures), the highest of which was 7.66% in 2011 and the lowest of which was 5.48% in 2013. The prevalence of fungal bloodstream infections was 0.38% (81/21,098), the highest of which was in 2016 at 0.47% and the lowest of which was in 2008 at 0.26% (Table 1).

Distribution of fungal strains

Over the 10-year study period, 98 fungal strains from bloodstream infections, mainly Candida spp., were obtained from the blood cultures from 81 ICU patients. Candida albicans was most common (42/98, 42.9%), followed by C. tropicalis (18/98, 18.4%), C. glabrata (12/98, 12.2%), C. parapsilosis (9/98, 9.2%), C. krusei (5/98, 5.1%), and C. guilliermondii (3/98, 3.1%). Over the 10-year study period, the prevalence of C. albicans decreased, while other Candida spp. increased each year (Fig. 1). In addition, three strains of Cryptococcus neoformans, two of Talaromyces marneffei, three of Pichia pastoris, and one of Saccharomyces cerevisiae were isolated.

Antimicrobial susceptibility of strains

The drug sensitivity analysis of the five main fungi in the 98 strains showed that >95% of C. albicans strains were sensitive to all antifungal agents tested. All strains of C. tropicalis were sensitive to caspofungin and amphotericin B, and >90% were sensitive to azoles. Candida glabrata were relatively less sensitive to azoles; 66.6% were sensitive to fluconazole and itraconazole, while all strains were sensitive to caspofungin and amphotericin B. Of the C. parapsilosis strains, 83.3% were sensitive to caspofungin, and all were sensitive to the other antifungals (Table 2).

Risk factor analyses

Twenty-nine of the 81 patients with fungal bloodstream infections in ICU died—a mortality rate of 35.8%. Univariate analysis of mortality risk factors showed that advanced age, diabetes, cardiovascular disease, lower serum albumin, elevated γ-gamma glutamyl peptidase, APACHE II score, three or more underlying diseases, catheter indwelling time, and ICU stay were associated with the death rates (all P < 0.05, Table 3). Sex, malignant tumor, COPD, digestive tract disease, urinary tract disease, hypertension, serum urea nitrogen, tracheal intubation, multilumen catheter, central venous catheter, gastrointestinal nutrition, emergency catheterization, blood transfusion, central venous catheter, patients in shock receiving cathecholamines etc, and combined use of antibiotics were found not to be associated with death from fungal bloodstream infections (Table 3).

Following multivariate logistic regression, age (odds ratio [OR] = 1.218, 95% confidence interval [CI] 1.013–1.465, P = 0.036), low serum albumin (OR = 0.639, 95% CI 0.455–0.897, P = 0.010), APACHE II score (OR = 6.330, 95% CI 1.821–22.001, P = 0.004), three or more combined underlying diseases (OR = 0.003, 95% CI 0.000–0.576, P = 0.030), and ICU time (OR = 1.322, 95% CI 1.020–1.714, P = 0.035) were independently associated with mortality during hospitalization (Table 4).

ROC analysis of APACHE II score and serum albumin

APACHE II score and serum albumin were the factors most strongly associated with mortality among patients with fungal bloodstream infections. After subjecting these variables to ROC analysis, the results showed that when the APACHE II score was >19, the area under the curve (AUC) was 0.801, and when serum albumin was ≤25 g/L, AUC was 0.636, which indicated that these were the best predictors for mortality among fungal bloodstream infection patients (Fig. 2).

A lot of literature[4-7], including our research conclusions, shows that the incidence of fungal bloodstream infection and the positive rate of blood culture are increasing year by year. The possible causes are mainly related to the continuous improvement of global medical standards and changes in the global environment [6,7,10,11]. First, the level of diagnosis has increased, and some bloodstream infections that were not found before can now be discovered. Second, all kinds of difficult surgery may not be carried out before, and now it can be carried out, the insertion operations were more, and the use of drugs such as hormones and immunosuppressive agents were more extensive, which will inevitably lead to an increase in fungal infections. Third, after the medical level was improved, the average life expectancy of humans has increased, a lot of literature indicates [21-23] that age was one of the independent risk factors for fungal bloodstream infection. Another important reason may be the change in environmental and social conditions. The first was serious pollution such as air, soil and water quality, which maked respiratory diseases and tumors show a growing trend. These diseases are one of the important risk factors for fungal bloodstream infections [6,7,11,12]. Secondly, the global economy had developed and productivity had increased greatly. Many people Physical labor was reduced, high-fat and high-calorie diets are increased, and basic diseases such as diabetes and high blood pressure are increasing. These diseases are also one of the risk factors for fungal bloodstream infections [6,7,11,12].

Although the management of invasive fungal infections has made considerable progress in recent years, the prevalence of these infections continues to significantly increase, which warrants close attention from medical care providers. The incidence rate of fungal bloodstream infections in ICU patients in developing countries is 4 to 15 times higher than that in developed countries [3]. In this study, the prevalence of fungal bloodstream infections in ICUs in the three hospitals surveyed in Meizhou from 2008 through 2017 was 0.38%. Compared with fungal bloodstream infections in ICU in developing countries, where the prevalence ranges from 0.22 to 4.1% [5–8], those in Meizhou were low and more comparable to the prevalence among developed countries, where the rates are reported to be 0.024–0.687% [9–11].

Our study results showed that the prevalence of fungal bloodstream infections was lowest in 2008 and highest in 2016, with an overall increasing trend. This might be related to the large-scale use of broad-spectrum antibiotics, corticosteroids, and immunosuppressive agents and to the rapid increase in immunocompromised populations in recent years. In addition, ICU stays are associated with various invasive procedures that carry increased risk of bloodstream infections, such as indwelling catheters, tracheotomy, mechanical ventilation, and hemodialysis [4,12–15].

The 98 strains of fungi isolated from ICU blood cultures were predominantly Candida spp., accounting for 90.8% (89/98) of all strains. Nearly one-half were C. albicans (42.9%), leaving 48.0% that comprised C. tropicalis, C. glabrata, and C. parapsilosis. The proportion of non-albicans species increased over the study period to comprise mainly C. tropicalis and C. parapsilosis, which is similar to the results of other reports [9,12–15].

Candida albicans were more sensitive to azole drugs, such as fluconazole, than other Candida spp. Because azole drugs are those most commonly used for clinical fungal treatment, this might explain the increase in the proportion of non-albicans infections. Candida tropicalis has a high infection rate in tropical Asia [8,32]. The Meizhou area is located in the southern part of China and has a subtropical climate, which might contribute to the high rate of ICU fungal infections in that area. Other reports show that C. parapsilosis is frequently carried on the hands of medical staff and has a tendency to form a biofilm on medical devices, which might explain its increasing prevalence in the area [16–17].

In this study, nine patients were also infected with Cr. neoformans, Ta. marneffei, Pi. pastoris, and S. cerevisiae. Although the pathogenic ability of Cr. neoformans and Ta. marneffei was strong, that of Pi. pastoris and S. cerevisiae was weak. Pichia pastoris is used mainly as a research vector and is rarely isolated from human blood.

Most guidelines recommend the use of echinomycin for antifungal infections [18]; however, fluconazole is the most commonly used antifungal drug, and although it has a high mortality rate when used to treat candidemia, it is still widely used in developing countries [19]. In an Indian multicenter study of ICU-acquired candidemia, 64% of the patients were treated with fluconazole [20]. In this study, although most Candida spp. were more sensitive to azole drugs, the susceptibility of C. glabrata to azole drugs was relatively low, which suggests that testing for antimicrobial susceptibility is necessary for the correct selection of antifungal drugs.

ICU patients have a relatively high mortality rate, often from infections. In addition, a variety of invasive procedures such as indwelling catheter, tracheotomy, mechanical ventilation, and hemodialysis, as well as organ transplantation and other new technologies, have become more common. The lack of early fungal diagnostic techniques in many hospitals has affected the early diagnosis and treatment of fungal bloodstream infections; consequently, the incidence of fungal bloodstream infections has rapidly increased, resulting in a higher mortality rate [17–20].

Age is a significant risk factor for nosocomial infections [21], particularly fungal infections of the bloodstream [22, 23]. Candida parapsilosis more frequently infects younger populations, while C. glabrata and C. tropicalis are more common among the elderly [16]. In this study, age was an independent risk factor for infection, and the mortality risk increased with age (Table 4) for several reasons. First, older patients are more likely to have underlying diseases, low immunity, and decreased organ function, which would make them more susceptible to fungal bloodstream infections. Second, older patients might be given fewer antifungal treatments than younger patients, the practice of which is independently associated with a poor prognosis[33].When the patient’s condition deteriorates, the elderly patient or his or her guardian might decide to stop treatment if the patient’s chance of recovery is low, the costs are higher if treatment is continued, or the patient’s medical insurance does not cover the antifungal drug. Poor care of elderly patients by society and family members, as well as the relatively lagging development of the medical insurance industry, are important problems that affect the health of the elderly in China [34]. To effectively reduce the high mortality rate for elderly patients with fungal disease, measures should be taken to resolve the above-mentioned problems and ensure that antifungal treatment is administered.

Studies have shown that diabetes, tumors, neutropenia, and chronic renal insufficiency are risk factors for fungal bloodstream infections [24, 25]. In this study, diabetes, cardiovascular disease, and three or more underlying diseases were strongly associated with mortality from the infection (Table 3). Logistic multiple regression analysis showed that three or more underlying diseases were among the independent risk factors (Table 4), which might be associated with patients with multiple long-term underlying diseases and many iatrogenic invasive procedures. Treatments such as recent surgery, solid organ transplantation, hemodialysis, longer ICU stay (≥7 d), mechanical ventilation, use of cardiovascular catheters, total parenteral nutrition, and catheters are other suggested risk factors for fungal bloodstream infections [26,27]. We found that length of stay in the ICU was also an important risk factor for mortality.

The APACHE II score is an important system used to determine the severity of a disease and estimates of mortality and plays an important role in judging the prognosis of bloodstream infections [28]. The higher the APACHE II score, the lower the patient’s immune function; the higher the probability of infecting pathogens, such as fungi; and the higher the chance of death. Serum albumin levels are also important factors that affect bloodstream infections in hospitals [29–31] and are associated with increased mortality from candidemia [32]. Low serum albumin levels affect the body’s immune function, including barrier function, leukocyte phagocytosis, and complement function, resulting in prolonged infection time, anti-infective effects, and increased mortality. Hypoalbuminemia can lead to serious complications, such as sepsis and septic shock [29–30]. The results of this study showed that the APACHE II score and serum albumin levels were two important independent mortality risk factors in ICU fungal infections (Table 4). According to our findings, we recommend that patients with APACHE II scores > 19 and serum albumin < 25 g/L should receive immediate clinical attention and increased vigilance for possible cases of fungal bloodstream infections.

Candida albicans, C. tropicalis, and C. parapsilosis were found to be the most common pathogens that cause fungal bloodstream infections in ICU patients in Meizhou, Guangdong, China. The common fungi in this area are highly sensitive to common antifungal drugs, but attention should be paid to the low sensitivity of C. glabrata to azole drugs and the resistance of C. parapsilosis to caspofungin. In addition, advanced age, serum albumin, APACHE II score, three or more combined underlying diseases, and ICU stay were independent risk factors for fungal bloodstream infections, each of which must be highly assessed in clinical practice. For high-risk groups, emphasis should also be placed on patient monitoring and risks of infection.

Study Limitations

Our study had several limitations. First, the design of the study limited our access to information on the use of antifungal drugs before hospitalization, and these data could be important for analyzing the emergence of antifungal resistance of the non-albicans species, for example, C. glabrata. Second, we analyzed only the presence or absence of exposure to certain risk factors for patient death instead of the duration of exposure. Because the study was not designed to quantify exposure time and the variable was not available for analysis, its associated bias could not be determined. Third, whether patients with fungal bloodstream infections carry AIDS and its related indicators is also an important factor in the death of patients, but in this study, only 2 cases (all deaths) were carried out with AIDS, and fewer cases were not included on analysis of the risk factors for patient mortality. Analysis of risk factors, which may be quite different from studies in other regions. In addition, because of differences in the epidemiological characteristics of antifungal use and candidemia in different countries and regions, we might not be able to extend some of our conclusions to other countries and regions, and additional research is needed in different geographical regions.

APACHE II: Acute Physiology and Chronic Health Evaluation II; ROC:Receiver Operating Characteristics ;COPD: Chronic Obstructive Pulmonary Disease;

Acknowledgements

The authors would like to thank Shanghai Key Laboratory of Medical Fungal Molecular Biology Open Project Foundation for funding support for research and the provision of data from various hospitals in Meizhou.

Funding

This work was supported by the Shanghai Key Laboratory of Medical Fungal Molecular Biology Open Project Foundation (Grant 14DZ2272900) to Guangwen Xiao. The funders played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the other authors have any financial disclosures.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

G Xiao planned the study, wrote the protocol, analysed the data, and wrote the report. W Liao gave guidance on the design of the study and revised the manuscript.Y Zhang, C Zhang and Y Xu were involved in collecting .X Luo, G Li and Y Yang were involved in analysing data and translating.All authors read and approved the final manuscript.

Ethics approval and consent to participate

The study was approved by the local institutional review board of the Medical College, Jiaying University; informed consent was not required from patients because of the observational nature of the surveillance.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

1Medical College, Jiaying University, Meizhou, People’s Republic of China.

2Shanghai Key Laboratory of Medical Fungal Molecular Biology, Shanghai, People’s Republic of China.

3The First Department of Anesthesiology, People’s Hospital of Meizhou, Meizhou, People’s Republic of China.

4Department of Anesthesiology, Chinese Medical Hospital of Meizhou, Meizhou, People’s Republic of China.

5Department of Cardiology, Yuedong Hospital the Third Affiliated Hospital of Sun Yat-Sen University, Meizhou, People’s Republic of China.

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Table 1. Prevalence of intensive care unit (ICU) fungal bloodstream infection by year from 2008 to 2017.

Year	Total blood culture (n)	Positive result (n/%)	Fungal positive (n/%)
2008	1,557	112 (7.20%)	4 (0.26%)
2009	1,571	109 (6.94%)	5 (0.32%)
2010	1,746	113 (6.47%)	6 (0.34%)
2011	1,672	128 (7.66%)	6 (0.36%)
2012	1,914	121 (6.32%)	8 (0.42%)
2013	2,135	117 (5.48%)	7 (0.33%)
2014	2,301	158 (6.87%)	10 (0.43%)
2015	2,503	147 (5.87%)	10 (0.40%)
2016	2,740	190 (6.93%)	13 (0.47%)
2017	2,959	185 (6.25%)	12 (0.41%)
Total	21,098	1,380 (6.54%)	81 (0.38%)

Table 2. Susceptibility rates of main fungi to five kinds of antifungal drugs (%).

Fungal species	Number of strains (n)	Susceptibility rate (%)
Fungal species	Number of strains (n)	caspofungin	Amphotericin B	Fluconazole	Voriconazole	Itraconazole
Candida albicans	42	100	97.6	95.2	97.6	100
Candida tropicalis	18	100	100	88.8	94.4	94.4
Candida parapsilosis	12	83.3	100	100	100	100
Candida glabrata	9	100	100	66.6	77.7	66.6

Table 3. Univariate analysis of mortality risk factors in patients in the intensive care unit with fungal bloodstream infections.

Variable	Survival (n = 52)	Death (n = 29)	χ²/F	P
Sex, male/female (n)	32/20	18/11	0.002	0.962
Age (years; mean ± s.d.)	56.9 ± 10.4	65.7 ± 11.8	10.619	0.001
Disease factors
Diabetes (n)	10	12	4.616	0.032
Malignant tumor (n)	3	4	1.518	0.218
Cardiovascular disease (n)	8	16	14.135	0.000
Chronic obstructive pulmonary disease (COPD) (n)	5	4	0.329	0.566
Digestive tract disease (n)	5	4	0.329	0.566
Urinary system disease (n)	8	6	0.366	0.545
Hypertension (n)	13	13	3.358	0.067
Serum albumin (g/L)	39.5 ± 8.6	33.1 ± 10.7	7.91	0.005
Serum urea nitrogen (μmol/L)	19.1 ± 27	30.7 ± 53.2	1.693	0.193
γ-gamma glutamyl peptidase (U/L)	36.2 ± 24.7	63.8 ± 67.6	6.629	0.010
Acute Physiology and Chronic Health Evaluation (APACHE) II score	16.32 ± 1.74	19.97 ± 2.90	31.565	0.000
Merger of three or more underlying diseases (n)	6	12	7.82	0.005
Invasive operative factors
Tracheal intubation (n)	16	13	1.601	0.206
Multi cavity catheter (n)	11	11	2.649	0.104
Central venous catheterization (n)	23	16	0.893	0.345
Catheter retention time (d)	12.0 ± 4.0	14.6 ± 5.8	5.070	0.024
Therapeutic factors
Hospitalization time in ICU (d)	9.7 ± 3.8	12.1 ± 6.7	4.401	0.036
Gastrointestinal nutrition (n)	21	14	0.472	0.492
Emergency tube (n)	18	14	1.454	0.228
Blood transfusion (n)	17	12	0.611	0.434
Central venous catheter(n)	33	20	0.249	0.804
Patients in shock receiving cathecholamines etc (n)	20	15	1.334	0.350
Combined use of antibiotics (n)	25	18	1.464	0.254

Notes: χ2/F, chi-squared value; P, probability.

Table 4. Logistic multiple regression analysis of mortality risk factors in patients in the intensive care unit (ICU) with fungal bloodstream infections.

Variable	Wald χ²	P	OR	95% CI
Age	4.380	0.036	1.218	1.013-1.465
Diabetes	3.106	0.078	19.544	0.717-533.069
Cardiovascular disease	0.079	0.779	0.698	0.057-8.610
Hypertension	0.882	0.346	6.494	0.131-322.387
Serum albumin	6.679	0.010	0.639	0.455-0.897
γ-gamma glutamyl peptidase	2.254	0.133	1.047	0.986-1.112
Acute Physiology and Chronic Health Evaluation (APACHE) II score	8.163	0.004	6.330	1.821-22.001
Three or more underlying diseases	4.560	0.030	0.003	0.000-0.576
Catheter retention time	2.607	0.064	1.307	0.984-1.737
Hospitalization time in ICU	4.052	0.035	1.322	1.020-1.714

Notes: Wald χ², chi-squared test value; OR, odds ratio; CI, confidence interval.

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Analysis of fungal bloodstream infection in intensive care units in the Meizhou region of China: species distribution and resistance and the risk factors for patient mortality

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